Systematic Identification of Immune-Related SnoRNAs: Potential Dual Roles in Tumor Progression and Immunotherapy Response

Background: Immune-related snoRNAs remain largely uncharacterized in cancer. Methods: We comprehensively investigated their functions and clinical relevance through an integrative pan-cancer analysis of The Cancer Genome Atlas (TCGA) datasets. We systematically identified immune-related snoRNAs via partial correlation with immune pathways and GSEA, validated their functions in vitro, and performed molecular subtyping in non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSC). Results: We established a comprehensive landscape of immune-related snoRNAs associated with core immune pathways, the majority of which were dysregulated across cancers and correlated with tumor immune cell infiltration. Functional screening revealed that numerous immune-related snoRNAs were aberrantly expressed in cancer stem cells; notably, SNORD116-19 potently suppressed breast cancer stemness and metastasis. Using a panel of immune-related snoRNAs, we classified NSCLC into three molecular subtypes with distinct molecular features and immune microenvironments, suggesting divergent immunotherapy response patterns. This classification framework was successfully extrapolated to HNSC. Conclusions: Our findings suggest that immune-related snoRNAs may serve as potential regulators linking tumor progression and immunity and could be explored as candidate biomarkers for molecular subtyping with the potential to inform personalized immunotherapy strategies.